Aqueous formulations of (2-hydroxymethyl-indanyl-4-oxy)-phenyl-4,4,4-trifluorobutane-1-sulfonate

ABSTRACT

The invention relates to aqueous formulations containing (−)-(R)-3-(2-hydroxymethyl-indanyl-4-oxy)-phenyl-4,4,4-trifluobutane-1-sulfonate. Said formulations are suitable as infusion solutions or as concentrate for producing these infusion solutions.

The present invention relates to(−)-(R)-3-(2-hydroxymethylindanyl-4-oxy)phenyl4,4,4-trifluorobutane-1-sulfonate-containing aqueous formulations whichare suitable as infusion solutions or as concentrate for preparing suchinfusion solutions.

(−)-(R)-3-(2-Hydroxymethylindanyl-4-oxy)phenyl4,4,4-trifluorobutane-1-sulfonate is a compound of the formula

As a cannabinoid receptor agonist, the compound (I) is suitable for theprevention and treatment of stroke and craniocerebral trauma; it wasdescribed for the first time in example 278 of WO 98/37061. Aqueouspharmaceutical preparations suitable for parenteral administration are,however, not disclosed in WO 98/37061. Since it is advantageous in theacute treatment of stroke and craniocerebral trauma to administer themedicament as infusion solution, there was a need for aqueousformulations containing the compound (I) and appropriate for thispurpose of use.

Remarkably, aqueous formulations of the compound (I) show aninhomogeneous concentration distribution. This means that, especially atlow active ingredient concentrations of a few milligrams per liter, itmust be assumed that an infusion rate which is constant based on thedose cannot be ensured over the complete infusion time. Thedisadvantages associated therewith are obvious.

For single-dose pharmaceutical forms, including parenteral powders andsuspensions for injection, the pharmacopeias (Ph. Eur. 4, 2002) requiretesting for uniformity of content, a deviation which is as low aspossible and does not exceed ±15% from the average of the activeingredient content.

It has surprisingly been found that the addition of cyclodextrin toaqueous formulations led to uniform concentration.

The invention thus relates to aqueous formulations comprising compound(I) and cyclodextrin.

Cyclodextins and methods for preparing them are disclosed in U.S. Pat.No. 3,453,259, U.S. Pat. No. 3,459,731, WO 97/39770, U.S. Pat. No.5,670,530, WO 96/32135, EP-B 149 197 and U.S. Pat. No. 4,727,064.Cyclodextrins are cyclic oligosaccharides which are formed in thedegradation of starch by cyclodextrin glycosyl transferases.

β-Cyclodextrins contain seven α-1,4-linked glucose units. The 21 hydroxygroups present in this molecule can be wholly or partly substituted forexample with optionally substituted aliphatic C₂-C₆ groups, preferablywith hydroxypropyl or sulfobutyl groups. The cyclodextrins used in thiscase preferably have an average degree of substitution (DS) per moleculeof from 1 to 10, in particular from 3 to 8.

The term “cyclodextrin” for the purposes of the invention includes theunsubstituted, the partially and the completely substitutedcyclodextrins, especially hydroxypropyl- and sulfobutyl-substitutedβ-cyclodextrins.

Surprisingly, it additionally emerges that physiologically toleratedacids are able to increase the storage stability of the aqueousformulations.

Examples of such physiologically tolerated acids include mineral acidssuch as, for example, hydrochloric acid, sulfuric acid, mono- to 4-basicsaturated and unsaturated C₂-C₁₀-carboxylic acids such as, for example,acetic acid, succinic acid, maleic acid, fumaric acid, C₂-C₆-hydroxycarboxylic acids such as, for example, malic acid, citric acid, glycolicacid, lactic acid, tartaric acid, cinnamic acid, C₃-C₆-keto carboxylicacids such as, for example, pyruvic acid, mono- or dibasic C₂-C₁₀-aminoacids such as, for example, alanine, aspartic acid, glutamic acid,glycine, isoleucine, leucine, lysine, methionine, phenylalanine,proline, serine, threonine, valine, C₆-C₁₂-amido carboxylic acids suchas, for example, hippuric acid, C₄-C₁₀-lactones such as, for example,ascorbic acid, and mixtures thereof. Lactic acid and citric acid arepreferred; citric acid is particularly preferred.

A preferred pH range for the aqueous formulations of the invention isfrom 2 to 6, in particular 3 to 5 and specifically about 3.5 to 4.5.

To prepare an isotonic solution, the formulations of the invention cancomprise compounds suitable for this purpose, such as, for example,glucose, mannitol, preferably sodium chloride. A solution is referred toas isotonic when it has an osmotic pressure of from 250 to 500,preferably 270 to 350, mosmol/kg.

Preferred isotonic formulations of the invention comprise from 5 to 15,preferably 7 to 13 and particularly preferably 8 to 10 g/l sodiumchloride, based on the formulation ready for use.

It is additionally possible to add to the formulations of the inventionphysiologically tolerated organic solvents, for example polyethyleneglycols, propylene glycol, glycofurol, glycerol or—preferably—alcohols,especially ethanol.

The formulations of the invention may generally comprise from 0.05 to 2,preferably 0.1 to 1.5 and in particular about 0.6 to 1.0 g/l organicsolvent based on the formulation ready for use.

The formulations of the invention may be in the form of infusionsolutions ready for use or of aqueous concentrates from which theinfusion solutions can then be prepared by adding water or isotonicelectrolyte solution. These concentrations of the invention may comprisethe compound (I) in a concentration of from 0.002 to 9.0, preferablyfrom 0.01 to 0.05, particularly preferably of 0.025 g/l. Theconcentrates may comprise cyclodextrin in concentrations of from 4 to550, preferably from 20 to 200, particularly preferably of 50 g/l. Ahomogeneous solution can be prepared from the concentrates easily andquickly under sterile conditions and is suitable directly for use, forexample as infusion solution.

The formulation of the invention may comprise cyclodextrin in 0.1 to 60,preferably 1 to 30, particularly preferably 1 to 10, in particular 2 g/lbased on the formulation ready for use.

The solubility of the compound (I) in water is 0.002 g/l at 25° C.

The formulation of the invention ready for use for infusion may comprisean active ingredient concentration of from 0.00005 to 0.002, preferably0.0001 to 0.002, in particular 0.0005 to 0.0015 and very specificallyabout 0.001 g of compound (I)/l of solution.

The formulations of the invention can be prepared simply by mixing anddissolving the components.

It has generally proved advantageous to administer the compound (I) intotal amounts of about 0.001 to about 240, preferably 0.01 to 24 μg/kgof body weight every 24 hours, where appropriate in the form of aplurality of single doses, to achieve the desired result.

It may, however, be advantageous where appropriate to deviate from thestated amounts, and in particular to do so as a function of the natureand body weight of the treated patient, of the individual behaviortowards the medicament, the nature and severity of the disease, the modeof preparation and administration, and the time or interval over whichadministration takes place.

The invention further relates to an administration kit consisting of acontainer comprising the aqueous formulation and of an infusionapparatus. The infusion apparatus consists in the simplest case of aneedle, connecting tubes, and a drip chamber. An infusion pump andregulating stopcocks can be attached to the connecting tubes.Administration is additionally possible by means of syringe driverscomprising infusion syringes with attached connecting tubes.

The materials of the administration kit which come into contact with theproduct can consist for example of polyethylene (PE), polypropylene(PP), polyamides, polyesters or copolymers thereof,acrylonitrile-butadiene-styrene copolymers,polypropylene/styrene-ethylene-butylene-styrene, preferably ofpolyolefins, particularly preferably of polyethylene.

EXAMPLES

1) Example of an Infusion Formulation Ready for Use and Based onhydroxypropyl-β-cyclodextrin Composition (in g/l) Compound (I) 0.001Hydroxypropyl-β-cyclodextrin (® Cavitron 82004, Cerestar) 2 Sodiumchloride 9 Ethanol for inj. 0.8 Citric acid 0.016 Water 993.383

Preparation: a solution of compound (I) in ethanol is added withstirring to an aqueous solution of hydroxypropyl-β-cyclodextrin andsodium chloride. The pH is adjusted to about 4 with citric acid. Thesolution is sterilized by filtration, dispensed into 250 ml glassbottles, closed with rubber stoppers and crimped caps and thensterilized in a steam autoclave at 121° C. for 20 min.

2) Example of an Infusion Formulation Ready for Use and Based onSulfobutyl Ether β-cyclodextrin Composition (in g/l) Compound (I) 0.001Sulfobutyl ether β-cyclodextrin (® Captisol, CyDex) 2 Sodium chloride 9Ethanol for inj. 0.8 Citric acid 0.016 Water 993.383

Preparation: a solution of compound (I) in ethanol is added withstirring to an aqueous solution of sulfobutyl ether β-cyclodextrin andsodium chloride. The pH is adjusted to about 4 with citric acid. Thesolution is sterilized by filtration, dispensed into 250 ml glassbottles, closed with rubber stoppers and crimped caps and thensterilized in a steam autoclave at 121° C. for 20 min.

3) Example of a Concentrate for Preparing an Infusion FormulationComposition (in g/l) Compound (I) 0.025 Hydroxypropyl-β-cyclodextrin(® Cavitron 82004, Cerestar) 50 Sodium chloride 9 Ethanol for inj. 0.8Citric acid 0.016 Water ad 1.01

Preparation: a solution of compound (I) in ethanol is added withstirring to an aqueous solution of hydroxypropyl-β-cyclodextrin andsodium chloride. The pH is adjusted to about 4 with citric acid. Thesolution is sterilized by filtration, dispensed into 10 ml glassbottles, closed with rubber stoppers and crimped caps and thensterilized in a steam autoclave at 121° C. for 20 min.

Before use, 10 mg of concentrate are mixed with 240 ml of physiologicalsaline solution. The result is an infusion solution ready for use withan active ingredient concentration of 0.001 g/l.

1. An aqueous formulation comprising(−)-(R)-3-(2-hydroxymethylindanyl-4-oxy)phenyl4,4,4-trifluorobutane-1-sulfonate (I) and cyclodextrin.
 2. A formulationas claimed in claim 1, comprising from 0.00005 to 9.0 g/l of thecompound (I) and from 0.1 to 550 g/l of cyclodextrin.
 3. A formulationas claimed in either of the preceding claims, comprising from 0.0001 to0.050 g/l of the compound (I) and from 0.2 to 200 g/l cyclodextrin.
 4. Aformulation as claimed in any of the preceding claims, comprising from0.0005 to 0.025 g/l of the compound (I) and from 1 to 50 g/lcyclodextrin.
 5. A formulation as claimed in any of the precedingclaims, which has a pH of from 2 to
 6. 6. A formulation as claimed inany of the preceding claims, comprising at least one physiologicallytolerated acid.
 7. A formulation as claimed in claim 6, which comprisescitric acid as physiologically tolerated acid.
 8. A formulation asclaimed in any of the preceding claims, comprising from 8 to 10 g/lsodium chloride based on the formulation ready for use.
 9. A formulationas claimed in any of the preceding claims, comprising from 0.05 to 2 g/lethanol based on the formulation ready for use.
 10. An administrationkit consisting of a) a container comprising the aqueous formulation asclaimed in claims 1 to 9, b) infusion apparatus, where at least theparts which come into contact with the product consist of polyethylene,polypropylene, polyester, polyamide, acrylonitrile-butadiene-styrenecopolymers, polypropylene/styrene-ethylene-butylene-styrene orcopolymers thereof.